| Background:Diabetic nephropathy (DN), as a serious chronic microvascular implication of diabetes mellitus (DM), has become the most principal contributor to end-stage renal disease (ESRD) with the increasing morbidity and mortality of DM. Multiple studies exist to prove that genetic factors and abnormal carbohydrate metabolism mainly contribute to the development of DN. Recently, engulfment and cell motility1(ELMO1) gene is identified to be a new candidate gene for DN in a Japanese genome-wide association study (GWAS), increasing susceptibility to DN and playing a vital role in the development of DN as well. Genetic associations at ELMO1are also shown in other GWAS of different countries, supporting its key role as a candidate gene in DN. In spite of that, no data related to the association of ELMO1polymorphisms with DN has been published in Chinese individuals. Since the specific nephropathy-associated variants and susceptibility as well as the distribution of genotype frequencies and allele frequencies of each single nucleotide polymorphism (SNP) site have differed in various races, it is necessary to conduct population-based studies with ELMO1gene in Chinese individuals.Objective:1. To explore the distribution of single nucleotide polymorphisms (SNP) sites of rs2058730(C/T), rs10951509(A/G), rs1981740(A/C), rs1345365(A/G), rs11769038(G/T) and rs741301(A/G) of ELMO1gene in Chinese Han population with type2diabetes mellitus.2. To discuss the association of the single nucleotide polymorphisms (SNP) sites of rs2058730(C/T), rs10951509(A/G), rs1981740(A/C), rs1345365(A/G), rs11769038(G/T) and rs741301(A/G) of ELMO1gene with the susceptibility of DN.Methods:Two hundred patients with type2diabetes mellitus (T2DM) were recruited in this study. Genotyping for rs2058730(C/T), rs10951509(A/G), rsl981740(A/C), rs1345365(A/G), rs11769038(G/T) and rs741301(A/G) of ELMO1gene of all subjects were accomplished by the SEQUENOM MassARRAY system based upon the chip-based matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS)(Sequenom, San Diego, CA, USA). According to urine albuminuric excretion rate (UAER), all T2DM subjects were divided into two groups:seventy-two T2DM patients without DN as DN-group and one hundred and twenty-three T2DM patients with DN as DN+group. Clinical characteristics, allelic and genotypic frequencies were compared between groups. Statistical analysis for each clinical characteristic was carried out using SPSS version16.0for Windows software package. Linkage disequilibrium (LD), haplotype construction, Hardy-Weinberg equilibrium (HWE) testing and allelic and genotypic frequency analysis were performed with SHEsis software by means of expectation-maximization algorithms.Results:1. Analysis of clinical characteristics in case group and control group. DN+group showed longer diabetes duration (P<0.01) and higher prevalence of hypertension than DN-group (P<0.05). Both groups had similar gender distribution, age, creatinine, family history, FPG, FIns, HbAlc, lipids, retinopathy rates, and application on the insulin and angiotensin-converting enzyme inhibitor (P>0.05).2. Distribution of allelic and genotypic frequency of each SNP site in the case-control cohort. Polymorphisms of rs10951509(A/G) and rs741301(A/G) in ELMO1gene in DN+group were significantly different from DN-group (P<0.05for both). While polymorphisms of rs2058730(C/T), rs1981740(A/C), rs1345365(A/G) and rs11769038(G/T) in ELMO1gene in DN+group were not significantly different from DN-group (P>0.05for all). The subjects with A allele of rs10951509had a higher risk of DN with1.76times to that of G allele carriers (OR=1.76,95%CI:1.08～2.87; P=0.02). While subjects with A allele of rs741301had a higher risk of DN with1.89times to that of G allele carriers(OR=1.89,95%CI:1.22-2.95; P=0.004).3. Logistic regression analysis. Logistic regression analysis showed that the rs741301polymorphism (presence of A allele, adjusted OR=3.27,95%CI:1.10-9.72; P=0.03) and duration of T2DM (adjusted OR=1.15,95%CI:1.01-1.32; P=0.04) were independent high risk factors for DN.4. Analysis of haplotype structure and frequency as well as parwise linkage disquilibrium of the6SNP loci. The marker rs741301of ELMO1gene was in strong LD with rs11769038(D’=0.91), and rs10951509was also in strong LD with rs1345365 (D’=0.98). The6SNP loci in ELMO1constituted nine haplotypes which accounted for more than85%of the population. What’s more, hapotype1[CAAAGA](OR=1.95,95%CI:1.15～3.32; P=0.01), hapotype2[C AAAG G](OR=0.50,95%CI:0.29～0.86; P=0.01) and hapotype9[T G C G G G](OR=0.17,95%CI:0.04～0.73; P=0.007) were significantly associated with DN, and the above haplotypes were highly concordant with those alleles at rs741301and rs10951509.Conclusions:1. Polymorphisms of rs10951509(A/G) and rs741301(A/G) in ELMO1gene might confer susceptibility to DN. Which suggests that ELMO1gene may be a candidate gene to DN.2. Logistic regression analysis showed that the presence of A allele of rs741301in ELMO1gene and the duration of T2DM were independent high risk factors for DN. Which suggests that subjects with A allele of rs741301in ELMO1gene as well as longer duration of T2DM had a higher risk of DN, and early prevention should be enhanced for them.3. The marker rs741301of ELMO1gene was in strong LD with rs11769038, and rs10951509was also in strong LD with rsl345365. Which suggests that multiple sites of the same gene may interact together, resulting in the development of DN.4. The6SNP loci in ELMO1constituted nine haplotypes, among which hapotype1[CAAAGA], hapotype2[C A A A G G] and hapotype9[T G C G G G] were significantly associated with DN. Which suggests that the above three hapotypes may be genetic markers to the risk forecasting in DN in Han population. |
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